The integrity of the FOG-2 LXCXE pRb-binding motif is required for small intestine homeostasis.

GATA transcription factors and their FOG cofactors play a key role in tissue-specific development and differentiation, from worms to humans. We have shown that GATA-1 and FOG-2 contain an LXCXE pRb-binding motif. Interactions between retinoblastoma protein (pRb) and GATA-1 are crucial for erythroid proliferation and differentiation, whereas the LXCXE pRb-binding site of FOG-2 is involved in adipogenesis. Fog2-knock-in mice have defective pRb binding and are resistant to obesity, due to efficient white-into-brown fat conversion. Our aim was to investigate the pathophysiological impact of FOG-2-pRb interaction on the small intestine and mouse growth. Histological analysis of the small intestine revealed architectural changes in Fog2(Rb-/Rb-) mice, including villus shortening, with crypt expansion and a change in muscularis propria thickness. These differences were more marked in the proximo-distal part of the small intestine and were associated with an increase in crypt cell proliferation and disruption of the goblet and Paneth cell lineage. The small intestine of the mutants was unable to adapt to a high-fat diet, and had significantly lower plasma lipid levels on such a diet. Fog2(Rb-/Rb-) mice displayed higher levels of glucose-dependent insulinotropic peptide release, and lower levels of insulin-like growth factor I release on a regular diet. Their intestinal lipid absorption was impaired, resulting in restricted weight gain. In addition to the intrinsic effects of the mutation on adipose tissue, we show here an extrinsic relationship between the intestine and the effect of FOG-2 mutation on mouse metabolism. In conclusion, the interaction of FOG-2 with pRb coordinates the crypt-villus axis and controls small intestine homeostasis.